BridgeBio Pharma, Inc. and Eidos Therapeutics, Inc. presented positive data from the companies' ongoing Open Label Extension (OLE) of the Phase 2 clinical trial studying AG10 in patients with symptomatic transthyretin (TTR) amyloidosis cardiomyopathy (ATTR-CM). ATTR-CM is a progressive and fatal disease that is an under recognized cause of heart failure. The data were presented in a late-breaking featured science oral presentation at the American Heart Association (AHA) Scientific Sessions in Philadelphia, Pennsylvania.

Study participants received 800mg of AG10 twice daily during the OLE and were followed for a median of 65 weeks since Phase 2 initiation. AG10 treatment was generally well-tolerated and resulted in near-complete TTR stabilization as measured using established ex vivo assays. Lower rates of mortality (death or cardiac transplantation) and cardiovascular-related hospitalizations were observed in AG10 Phase 2 OLE participants than were reported in a similar population of ATTR-CM patients who received placebo for 15 months in the ATTR-ACT study.

Cardiac biomarkers and echocardiographic parameters were stable in patients treated with AG10 in the Phase 2 OLE. AG10 Phase 2 Open Label Extension Results: The ongoing OLE study enrolled 47 of 49 participants (96%) from the 28-day randomized, placebo-controlled, Phase 2 study of AG10 in ATTR-CM patients with New York Heart Association (NYHA) Class II or III symptoms. Interim analysis of the ongoing study was completed on August 31, 2019 in conjunction with annual regulatory reporting and review, at which time 41 participants remained in the study. Three (6.4%) participants in the OLE had died, two due to disease progression and one due to cervical cancer.

Three (6.4%) additional patients enrolled in the study had discontinued treatment, including one participant who underwent cardiac transplantation for their disease. Adverse events reported in the OLE study were generally consistent with the underlying ATTR-CM disease state and no safety signals of potential clinical concern were associated with the administration of AG10 in the study. Forty-six (97.9%) patients experienced a treatment-emergent adverse event reported during the study, with falls, congestive cardiac failure, dyspnea, and acute kidney injury the most commonly reported adverse events.

Nineteen (40.4%) participants experienced a treatment-emergent serious adverse event reported during the study, with congestive cardiac failure (10.6%) and acute kidney injury (8.5%) the most commonly reported serious adverse events. The rate of all-cause mortality (including either death or cardiac transplantation, 8.5%) and cardiovascular-related hospitalizations (25.5%) observed in an exploratory analysis of participants in this study following a median of 15 months since Phase 2 initiation were lower than those observed at 15 months in placebo-treated patients in the ATTR-ACT study (all-cause mortality including death or cardiac transplantation, 15.3%; cardiovascular-related hospitalizations, 41.8%). Stabilization of TTR, as measured using established ex vivo assays, was maintained >90% on average at all study visits in actively treated patients.

Serum TTR levels, a prognostic indicator of survival in a published cohort of wild-type ATTR-CM patients, were elevated upon AG10 treatment and were maintained in the normal range throughout the study duration. Mean serum TTR levels were increased from baseline by 39% and 68% in wild-type and variant-carrying ATTR-CM patients, respectively, at OLE Visit Day 180. Cardiac biomarkers and echocardiographic parameters were stable during the OLE study.

NT-proBNP and TnI were unchanged throughout the course of the study. Echocardiographic parameters, including left ventricular mass and left ventricular stroke volume index, were unchanged during the study. A Phase 3 study of AG10 in ATTR-CM patients (ATTRibute-CM) is currently ongoing.

In Part A of the study, change in six-minute walk distance at 12 months will be compared between active treatment and placebo groups as the first registrational primary endpoint. In Part B, all-cause mortality and frequency of cardiovascular-related hospitalizations will be compared between treatment and control groups at 30 months total duration. In Part B, concomitant use of therapies indicated for the treatment of ATTR-CM may be allowed.

The study is enrolling at 44 sites across six countries and enrollment for Part A is now projected to complete in the second half of 2020, with top-line data expected in 2021. About AG10: AG10 is an investigational, orally-administered small molecule designed to potently stabilize tetrameric transthyretin, or TTR, thereby halting at its outset the series of molecular events that give rise to TTR amyloidosis, or ATTR. In a randomized, placebo-controlled Phase 2 clinical trial in patients with symptomatic ATTR-CM, AG10 was generally well tolerated, demonstrated greater than 90% average TTR stabilization at Day 28, and increased serum TTR concentrations, a prognostic indicator of survival in a retrospective study of ATTR-CM patients, in a dose-dependent manner.

The open label extension of this Phase 2 study identified no safety signals of potential clinical concern associated with administration of AG10 15 months after study initiation. In an exploratory analysis, lower rates of all-cause mortality (including death and cardiac transplantation) and cardiovascular hospitalizations were observed in study participants than in placebo-treated ATTR-CM patients in the ATTR-ACT study. Cardiac biomarkers and echocardiographic parameters were stable in the AG10 Phase 2 OLE.

AG10 was designed to mimic a naturally-occurring variant of the TTR gene (T119M) that is considered a rescue mutation because co-inheritance has been shown to prevent or ameliorate ATTR in individuals also inheriting a pathogenic, or disease-causing, mutation in the TTR gene. To knowledge, AG10 is the only TTR stabilizer in development that has been observed to mimic the stabilizing structure of this rescue mutation. The Phase 3 ATTRibute-CM study of AG10 in patients with ATTR-CM is underway.

Part A of the study will assess the change from baseline in 6-minute walk distance (6MWD) at 12 months. Part B of the study will evaluate reduction in all-cause mortality and frequency of cardiovascular-related hospitalizations at 30 months. In addition, Eidos plans to initiate a Phase 3 study of AG10 in ATTR polyneuropathy (ATTR-PN) in First Quarter 2020.

About transthyretin amyloidosis (ATTR): There is significant medical need in transthyretin amyloidosis (ATTR) given the large patient population and limited current standard of care. ATTR is caused by the destabilization of TTR due to inherited mutations or aging and is commonly divided into three distinct categories: wild-type ATTR cardiomyopathy (ATTRwt-CM), mutant ATTR cardiomyopathy (ATTRm-CM), and ATTR polyneuropathy (ATTR-PN).